Immunoglobulins from sera of APS patients bind HTR-8/SVneo trophoblast cell line and reduce additional mediators of cell invasion

Krivokuća, Milica Jovanović; Rabi, Tamara Abu; Stefanoska, Ivana; Vrzić-Petronijević, Svetlana; Petronijević, Miloš; Vićovac, Ljiljana

doi:10.1016/j.repbio.2017.10.006

Cited by 7 publications

(7 citation statements)

References 49 publications

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“… 10 , 11 Some experiments have shown that antibodies affect the cell invasion function of trophoblast cells. 12 , 13 In in vivo experiments in mice, the antibody entered the blood circulation and rapidly deposited in the foetal sacs, affecting mouse foetal cortical neuron cytoarchitecture. 14 The antibodies isolated from patients could cause foetal loss.…”

Section: Introductionmentioning

confidence: 99%

Protection by hydroxychloroquine prevents placental injury in obstetric antiphospholipid syndrome

Liu

Zhang

Tian

et al. 2022

J Cellular Molecular Medi

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Obstetric antiphospholipid syndrome (OAPS) is mediated by antiphospholipid antibodies (aPLs, and anti‐β2 glycoprotein I antibody is the main pathogenic antibody), and recurrent abortion, preeclampsia, foetal growth restriction and other placental diseases are the main clinical characteristics of placental pathological pregnancy. It is a disease that seriously threatens the health of pregnant women. Hydroxychloroquine (HCQ) was originally used as an anti‐malaria drug and has now shown benefit in refractory OAPS where conventional treatment has failed, with the expectation of providing protective clinical benefits for both the mother and foetus. However, its efficacy and mechanism of action are still unclear. After clinical data were collected to determine the therapeutic effect, human trophoblast cells in early pregnancy were prepared and treated with aPL. After the addition of HCQ, the proliferation, invasion, migration and tubule formation of the trophoblast cells were observed so that the therapeutic mechanism of HCQ on trophoblast cells could be determined. By establishing an obstetric APS mouse model similar to the clinical situation, we were able to detect the therapeutic effect of HCQ on pathological pregnancy. The normal function of trophoblast cells is affected by aPL. Antibodies reduce the ability of trophoblast cells to invade and migrate and can impair tubule formation, which are closely related to placental insufficiency. HCQ can partially reverse these side effects. In the OAPS mouse model, we found that HCQ prevented foetal death and reduced the incidence of pathological pregnancy. Therefore, HCQ can improve pregnancy outcomes and reverse the aPL inhibition of trophoblast disease. In OAPS, the use of HCQ needs to be seriously considered.

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Section: Introductionmentioning

confidence: 99%

Protection by hydroxychloroquine prevents placental injury in obstetric antiphospholipid syndrome

Liu

Zhang

Tian

et al. 2022

J Cellular Molecular Medi

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“…In APS, the development of pregnancy morbidity is related to endothelial activation and dysfunction that induce defective placental formation; however, the effect of aPL on trophoblast cells is vital ( Abrahams et al, 2017 ; Quao et al, 2018 ). aPL reduce decidual endovascular trophoblast invasion ( Sebire et al, 2002 ), leading to early recurrent miscarriages in APS ( Abrahams et al, 2017 ; Jovanovic Krivokuca et al, 2017 ; Quao et al, 2018 ). Contrarily, aPL also induce pregnancy morbidity in the second and third trimester by inducing placental dysfunction that is evidenced by preeclampsia and/or intrauterine growth restriction ( Antovic et al, 2018 ; Chu et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Differences in Endothelial Activation and Dysfunction Induced by Antiphospholipid Antibodies Among Groups of Patients With Thrombotic, Refractory, and Non-refractory Antiphospholipid Syndrome

et al. 2021

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Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by pregnancy morbidity or thrombosis and persistent antiphospholipid antibodies (aPL) that bind to the endothelium and induce endothelial activation, which is evidenced by the expression of adhesion molecules and the production of reactive oxygen species (ROS) and subsequent endothelial dysfunction marked by a decrease in the synthesis and release of nitric oxide (NO). These endothelial alterations are the key components for the development of severe pathological processes in APS. Patients with APS can be grouped according to the presence of other autoimmune diseases (secondary APS), thrombosis alone (thrombotic APS), pregnancy morbidity (obstetric APS), and refractoriness to conventional treatment regimens (refractory APS). Typically, patients with severe and refractory obstetric APS exhibit thrombosis and are classified as those having primary or secondary APS. The elucidation of the mechanisms underlying these alterations according to the different groups of patients with APS could help establish new therapies, particularly necessary for severe and refractory cases. Therefore, this study aimed to evaluate the differences in endothelial activation and dysfunction induced by aPL between patients with refractory obstetric APS and other APS clinical manifestations. Human umbilical vein endothelial cells (HUVECs) were stimulated with polyclonal immunoglobulin-G (IgG) from different groups of patients n = 21), including those with primary (VTI) and secondary thrombotic APS (VTII) and refractory primary (RI+), refractory secondary (RII+), and non-refractory primary (NR+) obstetric APS. All of them with thrombosis. The expression of adhesion molecules; the production of ROS, NO, vascular endothelial growth factor (VEGF), and endothelin-1; and the generation of microparticles were used to evaluate endothelial activation and dysfunction. VTI IgG induced the expression of adhesion molecules and the generation of microparticles and VEGF. RI+ IgG induced the expression of adhesion molecules and decreased NO production. RII+ IgG increased the production of microparticles, ROS, and endothelin-1 and reduced NO release. NR+ IgG increased the production of microparticles and endothelin-1 and decreased the production of VEGF and NO. These findings reveal differences in endothelial activation and dysfunction among groups of patients with APS, which should be considered in future studies to evaluate new therapies, especially in refractory cases.

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“…This lectin has the ability to bind various ECM proteins, as well as cell surface adhesion molecules, including trophoblast integrin β1 [96]. Results obtained in our previous research on HTR-8/SVneo cells showed that Gal-1 was reduced in conditioned media of aPL IgG-treated cells, while total cell protein remained unaltered, suggesting that aPL IgG may affect Gal-1 secretion in a manner not yet elucidated [89]. We have shown that aPL IgG treatment activates the p38 MAPK signaling pathway, and that inhibitory effects on integrin subunits and secreted Gal-1 were dependent on this activation [89].…”

Section: Trophoblast Cell Functionmentioning

confidence: 95%

“…Further investigations showed that aPL-associated reduction in invasiveness could at least, in part, be attributed to downregulation in invasion mediators-integrin subunits α1, α5 and β1 [67,68,88,89]. MMP-2 and MMP-9 are highly expressed during implantation and early stages of pregnancy, playing a key role in the degradation of the extracellular matrix (ECM) by trophoblast cells [90,91].…”

Section: Trophoblast Cell Functionmentioning

confidence: 99%

“…MMP-2 and MMP-9 are highly expressed during implantation and early stages of pregnancy, playing a key role in the degradation of the extracellular matrix (ECM) by trophoblast cells [90,91]. Anti-β2GPI antibodies inhibited MMP-2 and MMP-9 secretion by trophoblast cells [66,68], while IgG from aPL-positive sera (aPL IgG) significantly decreased the level of MMP-9 and the overall gelatinolytic capacity of HTR-8/SVneo cells as assessed by in situ gelatin zymography [89]. Another possible mechanism of aPL-mediated invasion suppression is through downregulation of IL-6 secretion and STAT3 activity, as this was shown for mouse anti-β2GPI antibodies in HTR-8/SVneo cells [56].…”

Section: Trophoblast Cell Functionmentioning

confidence: 99%

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Trophoblast Cell Function in the Antiphospholipid Syndrome

Vrzić Petronijević,

Vilotić,

Bojić-Trbojević

et al. 2023

Biomedicines

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Antiphospholipid syndrome (APS) is a complex thrombo-inflammatory autoimmune disease characterized by the presence of antiphospholipid antibodies (aPL). Women with APS are at high risk of recurrent early pregnancy loss as well as late obstetrical complications—premature birth due to placental insufficiency or severe preeclampsia. Accumulating evidence implies that vascular thrombosis is not the only pathogenic mechanism in obstetric APS, and that the direct negative effect of aPL on the placental cells, trophoblast, plays a major role. In this review, we summarize the current findings regarding the potential mechanisms involved in aPL-induced trophoblast dysfunction. Introduction on the APS and aPL is followed by an overview of the effects of aPL on trophoblast—survival, cell function and aPL internalization. Finally, the implication of several non-coding RNAs in pathogenesis of obstetric APS is discussed, with special emphasis of their possible role in trophoblast dysfunction and the associated mechanisms.

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Immunoglobulins from sera of APS patients bind HTR-8/SVneo trophoblast cell line and reduce additional mediators of cell invasion

Cited by 7 publications

References 49 publications

Protection by hydroxychloroquine prevents placental injury in obstetric antiphospholipid syndrome

Protection by hydroxychloroquine prevents placental injury in obstetric antiphospholipid syndrome

Differences in Endothelial Activation and Dysfunction Induced by Antiphospholipid Antibodies Among Groups of Patients With Thrombotic, Refractory, and Non-refractory Antiphospholipid Syndrome

Trophoblast Cell Function in the Antiphospholipid Syndrome

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